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Regulation of Telomerase by Telomeric Proteins

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Regulation of Telomerase by Telomeric Proteins AR REVIEWS IN ADVANCE 10.1146/annurev.biochem.73.071403.160049 (Some corrections may occur before final publication online and in print) Annu. Rev. Biochem. 2004. 73:177–208 doi: 10.1146/annurev.biochem.73.071403.160049 Copyright © 2004 by Annual Reviews. All rights reserved First published online as a Review in Advance on April 2, 2004 REGULATION OF TELOMERASE BY TELOMERIC PROTEINS Agata Smogorzewska1 and Titia de Lange2 1Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02115; email: [email protected] 2The Rockefeller University, New York, New York 10021; email: [email protected] Key Words aging, cancer, human, telomere, yeast f Abstract Telomeres are essential for genome stability in all eukaryotes. Changes in telomere functions and the associated chromosomal abnormalities have been implicated in human aging and cancer. Telomeres are composed of repetitive sequences that can be maintained by telomerase, a complex containing a reverse transcriptase (hTERT in humans and Est2 in budding yeast), a template RNA (hTERC in humans and Tlc1 in yeast), and accessory factors (the Est1 proteins and dyskerin in humans and Est1, Est3, and Sm proteins in budding yeast). Telomerase is regulated in cis by proteins that bind to telomeric DNA. This regulation can take place at the telomere terminus, involving single-stranded DNA-binding proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to contribute to the recruitment of telomerase and may also regulate the extent or frequency of elongation. In addition, proteins that bind along the length of the telomere (TRF1/TIN2/tankyrase in humans and Rap1/Rif1/Rif2 in budding yeast) are part of a negative feedback loop that regulates telomere length. Here we discuss the details of telomerase and its regulation by the telomere. CONTENTS THE END REPLICATION PROBLEM ...........................178 THE CONSEQUENCES OF TELOMERE DYSFUNCTION ..............178 TELOMERE MAINTENANCE BY TELOMERASE...................179 TELOMERASE ACCESSORY FACTORS.........................182 TELOMERASE-INDEPENDENT TELOMERE LENGTH CHANGES ........183 REGULATION OF TELOMERASE AT THE TELOMERE TERMINUS: THE ROLE OF CDC13 .......................................183 TELOMERE LENGTH HOMEOSTASIS: CIS-ACTING CONTROL BY FAC- TORS BINDING TO DUPLEX TELOMERIC REPEATS...............187 Negative Feedback Control by the Yeast RAP1/RIF1/RIF2 Complex .........187 Negative Feedback Control by the Mammalian TRF1 Complex ...........190 TRF1 Partners: Tankyrase 1 and 2, TIN2, and PINX1 ................193 0066-4154/04/0707-0177$14.00 177 AR REVIEWS IN ADVANCE 10.1146/annurev.biochem.73.071403.160049 178 SMOGORZEWSKA y DE LANGE Telomere Length Control by POT1: Connecting the TRF1 Complex to the Telomere Terminus .....................................194 FROM YEAST TO MAN: DRASTIC CHANGES IN THE TELOMERE LENGTH CONTROL COMPLEX....................................198 DNA DAMAGE RESPONSE PATHWAYS AND THE CONTROL OF TELO- MERE MAINTENANCE...................................201 THE END REPLICATION PROBLEM The advent of linear chromosomes created a significant challenge for DNA replication. The problem, referred to as the end replication problem (1, 2), originates from the use of short RNAs to prime DNA synthesis. Removal of these primers results in 8–12 nucleotide (nt) gaps that do not impede the duplication of circular genomes because each gap can be closed by extending a preceding Okazaki fragment. However, on a linear template, the last RNA that primed lagging-strand synthesis will leave a gap that can not be filled. In the absence of a telomere maintenance system, many eukaryotes (fungi, trypanosomes, flies, mosquitos) lose terminal sequences at ϳ3–5 bp/end/division, a modest rate predicted by the end replication problem (3–6; G. Cross, personal communica- tion; J. Cooper, personal communication). Human and mouse telomeres shorten much faster (50–150 bp/end/cell division (7–9); this suggests that chromosome ends, in these organisms, might be actively degraded. If telomere erosion is not balanced by elongation, telomeres will progressively shorten, eventually leading to chromosome instability and cell death. Therefore, the long-term proliferation of all eukaryotic cells, including cells giving rise to the germline, requires a mechanism to counteract telomere attrition. Here we review the mechanisms by which telomeric DNA is maintained and discuss how telomere associated proteins regulate this process. THE CONSEQUENCES OF TELOMERE DYSFUNCTION The telomeric nucleoprotein complex allows cells to distinguish natural chro- mosome ends from DNA breaks [reviewed in (10, 11)]. Without telomere protection, chromosome ends activate DNA damage response pathways that signal cell cycle arrest, senescence, or apoptosis. Telomeres also prevent inap- propriate DNA repair reactions, such as exonucleolytic degradation and ligation of one end to another. When telomere function is impaired, fusion of unprotected chromosome ends can generate dicentric chromosomes, which are unstable in mitosis and wreck havoc in the genome. Telomeres have received considerable attention since the realization that changes in their structure and function occur during cancer development and aging. Many human cell types display telomere erosion, a process that is thought AR REVIEWS IN ADVANCE 10.1146/annurev.biochem.73.071403.160049 REGULATION OF TELOMERASE 179 to limit the proliferative capacity of transformed cells and has the hallmark of a tumor suppressor system. In most human cancer, the telomere barrier has been bypassed through the activation of a telomere maintenance system, making telomere replication an attractive target for therapeutic intervention. Although the programmed shortening of human telomeres may be effective in limiting the cancer burden early in life, the same program may have detrimental conse- quences late in life. In the aged, short telomeres are predictive of diminished health and longevity, and at least one human premature aging syndrome is associated with compromised telomere function (12, 13). Diminishing telomere function late in life may even promote genome instability and therefore contrib- ute to the higher incidence of cancer in the aged. The role of telomeres in cancer and aging has been reviewed extensively elsewhere (14, 15). TELOMERE MAINTENANCE BY TELOMERASE The most versatile and widely used method of telomere maintenance is based on telomerase (Figure 1) (16, 17). A two-component ribonucleoprotein enzyme, telomerase contains a highly conserved reverse transcriptase [telomerase reverse transcriptase, TERT, (18–20)] and an associated template RNA (telomerase RNA component, TERC, also referred to as TR or TER (21–24). TERT is most closely related to the reverse transcriptases of non-LTR retroposons and group II introns (23), and like these RTs, it extends the 3Ј end of a DNA rather than an RNA primer (25). The primer for telomerase is the chromosome terminus, which can be positioned on an alignment site in TERC such that the 3Ј end of the telomere is adjacent to the short (often 6 nt) template sequence (Figure 1A and B). Extension of the telomere terminus results in the addition of one telomeric repeat, and repeated alignment and extension steps can endow chromosome ends with the direct repeat arrays typical of telomeres. Although the sequence and size of telomerase RNAs are highly variable, they share structural motifs (Figure 1C) (26, 27), which may mediate the interaction with TERT, or control of the alignment, extension, and translocation steps. After elongation of the 3Ј end, C-strand synthesis is presumably required to create double-stranded telomeric DNA, but the details of this step have only been examined in ciliates [(28–30), reviewed in (31)]. In addition, Tetrahymena telomeres have a precisely defined terminal structure that is generated by nucleolytic processing (32, 33), and it will be interesting to learn whether similar terminus transactions are required in other organisms. In most unicellular organisms, telomerase has a housekeeping function, and its core components are always expressed. In contrast, telomerase is strongly suppressed in the human soma, a phenotype also observed in old world monkeys and new world primates (but not in prosimians, such as lemurs) [(18, 20, 34, 35); reviewed in (36)]. Robust telomerase activity is restricted to ovaries, testes, and highly proliferative tissues. This regulation place exists primarily at the level of AR REVIEWS IN ADVANCE 10.1146/annurev.biochem.73.071403.160049 180 SMOGORZEWSKA y DE LANGE AR REVIEWS IN ADVANCE 10.1146/annurev.biochem.73.071403.160049 REGULATION OF TELOMERASE 181 transcription of the hTERT gene; hTERC is virtually ubiquitous (24). The repression of hTERT transcription involves multiple genes previously implicated in tumorigenesis, which include Menin, the Mad/Myc pathway, and the TGF␤ target Sip1 [(37); reviewed in (38)]. Exogenous expression of hTERT in primary human fibroblasts is sufficient to reconstitute telomerase activity and to counteract telomere erosion. The resulting telomere maintenance immortalizes most human cell types (39–41). Like pri- mary cells, tumor cells require a telomere maintenance system for long-term proliferation, and in the majority of cases, this is provided by upregulation of hTERT [reviewed in (36)]. Telomerase activity per se does not induce transfor- mation (42), and although telomerase is necessary for immortalization, hTERT is not an oncogene (43, 44). Conversely, oncogenic
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